Faecal therapy back in vogue to treat superbugs

In 1958 Dr Ben Eiseman was faced with a situation he’d sadly encountered numerous times before. The 41-year-old Denver surgeon had four patients who were at death’s door, suffering from a life-threatening form of diarrhoea that had set in after antibiotic treatment. Eiseman knew his patients' chances of survival were slim, so having exhausted other options, including administering further doses of antibiotics, Eiseman and his colleagues decided to try something new.

They reasoned that the original antibiotic treatment that had brought on the diarrhoea must have done so by disrupting the delicate ecological balance of the bowels' resident micro-organisms. It was this imbalance that had allowed the rampant diarrhoea causing infection to thrive. So they sought to rectify this imbalance by providing the patients with a brand new set of microbes by performing a faecal microbiota transplant—otherwise known as faecal bacteria therapy, or a poo transplant.

A poo transplant is, as you can probably imagine, exactly what it sounds like—transferring faeces from a healthy donor to the colon of a recipient. It’s a simple idea, really: replace a depleted out-of-balance gut ecosystem with a robust and healthy one and balance is restored. And unlike blood transfusions and tissue transplants, faecal transplants require no immunological typing to prevent rejection. The idea was simple and as Eiseman and his colleagues discovered it was also highly effective. All four patients made swift and full recoveries and were discharged from the hospital within days of having the procedure.

You may well wonder, then, why you have not heard more about faecal transplants. In the 1960s as the field of organ transplantation forged ahead with the first pancreas transplant in 1966 and then liver and heart transplants in 1967, the humble poo transplant was all but forgotten. New antibiotics were developed in the late '50s and early '60s that effectively killed the unidentified bacteria responsible for hospital-acquired diarrhoea. Patients could once more be offered a pill or have an infusion rather than face the prospects of the procedure with the ultimate yuck factor.

But in recent years physicians have been rediscovering poo transplants. The main cause of pseudomembranous enterocolitis—the severe diarrhoea that Eiseman’s patients had in 1958 is a bacterium called Clostridium difficile or C.diff. A small number of people naturally harbour C.diff in their large intestine but far more acquire the bacteria in hospitals or nursing homes.

In recent years a highly toxic strain of C.diff has emerged in hospitals in North America. In 2010 it was estimated that half a million people per year in the US alone were infected with C.diff and up to 20,000 of those died from the infection. And as superbugs often do, C.diff has started to spread; cases in Europe and Australia are on the rise. Like it did in 1958, C.diff preys on people whose normal community of microbes has been wiped out by antibiotics. For one in four people with C.diffinfection, antibiotics offer only temporary relief, the obstinate infection returning with frustrating frequency. And for some, antibiotics have no effect at all. It is for these patients that doctors have been reprising the faecal microbiota transplantation.

And once again doctors are discovering what Eiseman and his colleagues did 50 years ago, that poo transplants work. A recent review of all reported studies of faecal transplants to treat C.diff infection found an overall success rate of over 90 per cent; recurrence is rare and there has not been a single report of adverse side effects. Perhaps more telling are the results from a clinical trial of the procedure where patients with C.diff infection were randomly selected to either have a faecal transplant or receive standard antibiotic treatment, the random allocation being a gold standard for clinical trials.

In this study, 94 per cent of patients receiving faecal transplants recovered after one or two procedures. Those receiving antibiotic treatment fared far worse with only 30 per cent recovering. The faecal transplants worked so much better than standard treatment that the trial was abandoned mid-way, the researchers deeming it unethical to knowingly give some trial participants a far less effective treatment.

But more than just being a quirky therapy that’s more reminiscent of leeches and bloodletting than modern day medicine, the poo transplant for me is an elegant illustration of the impressive complexity of the microbial communities that call us home and of how crucial these communities are in keeping us healthy. Each one of us harbours a stunning array of microbes that live on every body surface and in every nook and cranny available— in our mouth, on our skin and throughout our digestive tract. Estimates put the number at around 100 trillion. These invisible passengers—our microbiota—outnumber our own cells by about 10 to 1 when we consider just the bacteria, and 20 to 1 if we throw fungi and viruses into the mix.

Over recent years there has been a huge effort to understand what lives where and how these apparent freeloaders influence our health. Much of what has been discovered indicates that our microbiota aren’t freeloaders at all. The communities of friendly bacteria, or commensals, can be absolutely crucial for how our body functions, how it digests food and how it primes our immune system to fend off invaders such as C.diff. Some researchers have even suggested that we should consider ourselves and our microbes as one: a super-organism of human being and microbes, each unable to function fully with the other.

Two large scientific efforts to map these organisms, our microbiota and their collective genomes, the human microbiome, are currently underway. The Human Microbiome Project, funded by the National Institutes of Health in the United States, and the European Commission-funded Metagenomics of the Human Intestinal Tract project are beginning to define our most intimate microbial inhabitants asking questions such as what species are present, what functions do they carry out and how do they vary around the globe, across life spans and through illness and health. The sequencing effort alone is akin to re-running the human genome project ten times over. For every one gene that’s in your genome there are 100 bacterial genes working alongside. So, if we consider our body as a super-organism, then the genetic and metabolic diversity between each of us is suddenly enormous compared with the diversity present in our own genes.

Examining bacterial communities and their genes in such complexity hasn’t always been so simple. The traditional way of identifying and understanding microbes is to grow them in the lab a process known as culturing. The idea is that if you provide bacterial cells with the right nutrients and temperature to mimic what they would experience in their native environment, for example your large intestine, they should obligingly multiply and give you billions of themselves to pick and probe and experiment with. But this idea that we can pluck a single bacterial cell from the environment and nurture and cajole it to divide into a visible waxy spot thing in a Petri dish, or a cloudy swarm in nutrient broth, has its limits.

The reality for microbiologists is far more frustrating because we actually have no way of culturing a vast majority of the world’s micro-organisms. Although they grow very well inside our gut, many of the bacterial residents of our gastrointestinal tract are recalcitrant malcontents when it comes to traditional lab culturing techniques. Only about 20 per cent of our gut’s residents can be cultured in the lab.

Over the last two decades genomics has emerged as an invaluable tool in deciphering the biological world around us. High through-put sequencing technologies have been used to decode the genomes of a whole farmyard of creatures, humans included. Most recently we started extracting the genetic material from mixed specimens such as human faeces and we can let computer algorithms sort through the genetic quagmire to tell us exactly what creatures lurk within. Genomics has stepped in to do the heavy lifting where incubators and Petri dishes fall short.

By conducting a census of the bacteria living in our gut and by sequencing their genomes, we are beginning to understand what many have known for decades and what faecal transplants so elegantly illustrate: that there is an intimate association between our microbes and our health. Overall there are around 1000 species of bacteria that can be found in the human bowel, although the difference between one gut and the next can be enormous. Sixty-odd species are resident in the majority of people who have had their ecosystems sampled but the amount of each of these common lodgers can differ from one gut to the next by more than a thousandfold.

Humans and our microbiota have co-evolved over millennia, creating a co-dependent relationship. While we provide a cosy niche and abundant supply of food to the hordes in our intestine, they in turn help to release vital nutrients from otherwise indigestible dietary fibre and help to synthesise essential vitamins. It should come as no surprise that our diet plays an important role in determining which species choose to take up residence in our gut. People who eat a diet rich in carbohydrates have a different gut ecosystem to those with diets rich in proteins and fats. People who are obese have less diverse ecosystems than lean people and the composition of our gut microbiota can even signal a progression towards metabolic syndrome, the precursor to Type 2 Diabetes. In fact sampling the gut’s microbial genes might be a better predictor of Type 2 Diabetes than other risk factors such as body mass index, or BMI, or waist to hip ratio.

While diet is an obvious factor that can influence our gut microflora, other things such as our age and genetics, as well as which microbes we are exposed to as an infant and the environment that we live in, are all thought to play a role in determining the composition of our intestinal communities.

The question now being asked by the human microbiome projects are only new because of the communities in question—ecologists have been asking many of the same questions for decades. For example, how stable is each person’s gut ecosystem? What happens when a key organism is removed from the community? What does greater diversity in an ecosystem mean for the functioning of that ecosystem? And what does our reliance on antibiotics mean for our microscopic passengers and our own health? Perhaps, most importantly, how can we rectify things when they go wrong?

As researchers pore over the reams of data coming out of the microbiome labs around the world, a detailed picture of the microbes that make up the complex ecology of our gut will surely emerge. Maybe we will identify different species of bacteria that we can take as probiotics to treat different medical conditions. Or perhaps there are particular foods and supplements that we can consume as prebiotics to favour the growth of healthy bacteria in our gut. But in the meantime, the simplest and perhaps most obvious way of modifying our gut microflora when we are ill may well be to transfer an ecosystem en masse through the under-appreciated technique of the once forgotten poo transplant.

This script was originally delivered by Dr Dyani Lewis from the University of Melbourne's School of Population Health as part of Ockham's Razor, which you can listen to here.